Chronic liver disease and cirrhosis are a worldwide problem and the 12th leading cause of death in the U.S. Liver cirrhosis is preceded by fibrosis, which is a reversible, wound-healing response characterized by the synthesis of abnormal and excessive extracellular matrix by myofibroblasts. Liver myofibroblasts arise from the differentiation of heterogenous precursors, most notably hepatic stellate cells. Targeting myofibroblast differentiation is a logical strategy to limit fibrosis and enhance recovery from liver disease. However, the mechanisms that regulate myofibroblast differentiation are not completely understood, and currently there are no anti-fibrotic drugs approved for use in the U.S. We recently discovered that myofibroblast differentiation is increased by exogenous activation ofthe aryl hydrocarbon receptor (AhR). We will mechanistically determine how exogenous and endogenous AhR signaling impacts myofibroblast differentiation and liver fibrosis. We will test the hypothesis that AhR signaling is a regulator of myofibroblast differentiation. We will determine how AhR signaling regulates myofibroblast differentiation. We will test the possibility that a selective AhR modulator (SAhRM) holds promise for therapeutic use in suppressing myofibroblast differentiation using whole transcriptome sequencing and multiplex assays. We will determine how exogenous AhR activation enhances myofibroblast differentiation using well-established mouse models of liver fibrosis. We will determine if TCDD directly or indirectly targets myofibroblast differentiation during liver fibrosis using conditional AhR knockout mice in which the AhR is removed from either hepatic stellate cells or from parenchymal hepatocytes. As Junior Investigator in the COBRE in Matrix Biology, I will work with my scientific mentor to complete the aims and develop a grant proposal for future R01 funding.
Results from this project are expected to establish a new role for the AhR in regulating myofibroblast activation and liver fibrosis. Unveiling a novel AhR-mediated mechanism of regulating myofibroblast activation will address a critical barrier that has previously hindered the development of effective anti-fibrotic therapeutics
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